The present invention relates to the use of bi-cyclic pyrimidines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to processes for preparation of such pharmaceutical compositions. The present invention also concerns combinations of the present bi-cyclic pyrimidines with other anti-HCV agents.
Following its discovery in 1989 as the agent implicated in the majority of viral non-A, non-B hepatitis (Choo et al., Science 244, 359-362, 1989), hepatitis C virus (HCV) has become a focus of considerable medical research (Lauer, G. M and Walker, B. D., New Eng. J Med. 345, 41-52, 2001). HCV is a member of the Flaviviridae family of viruses in the hepacivirus genus, and is closely related to the flavivirus genus, which includes a number of viruses implicated in human disease, such as dengue virus and yellow fever virus, and to the animal pest virus family, which includes bovine viral diarrhea virus (BVDV). HCV is a positive-sense, single-stranded RNA virus, with a genome of around 9,600 bp. The genome comprises both 5′ and 3′ untranslated regions which adopt RNA secondary structures, and a central open reading frame that encodes a single polyprotein of around 3,010-3,030 amino acids. The polyprotein encodes ten gene products which are generated from the precursor polyprotein by an orchestrated series of co- and post-translational endoproteolytic cleavages mediated by both host and viral proteases. The viral structural proteins include the core nucleocapsid protein, and two envelope glycoproteins E1 and E2. The non-structural (NS) proteins encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function. Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by non-structural protein 5b (NS5B). In addition to the polymerase, the viral helicase and protease functions, both encoded in the bifunctional NS3 protein, have been shown to be essential for replication of HCV RNA in chimpanzee models of infection (Kolykhalov, A. A., Mihalik, K., Feinstone, S. M., and Rice, C. M. J Virol. 74, 2046-2051, 2000). In addition to the NS3 serine protease, HCV also encodes a metalloproteinase in the NS2 region.
HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection. There are 6 major HCV genotypes and more than 50 subtypes, which are differently distributed geographically. HCV type 1 is the predominant genotype in the US and Europe. For instance, HCV type 1 accounts for 70 to 75 percent of all HCV infections in the United States. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to therapy. An estimated 170 million persons worldwide are infected with hepatitis C virus (HCV). Following the initial acute infection, a majority of infected individuals develop chronic hepatitis, which can progress to liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma) (National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C. Hepatology, 36, 5 Suppl. S3-S20, 2002). Liver cirrhosis due to HCV infection is responsible for about 10,000 deaths per year in the U.S.A. alone, and is the leading cause for liver transplantations. Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use. The introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence. However, given the slow progression to the end-stage liver disease, the existing infections will continue to present a serious medical and economic burden for decades (Kim, W. R. Hepatology, 36, 5 Suppl. S30-S34, 2002).
The treatment of this chronic disease is an unmet clinical need, since current therapy is only partially effective and limited by undesirable side effects. Current HCV therapies are based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. This combination therapy yields a sustained virologic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and 3. Beside the limited efficacy on HCV type 1, combination therapy has significant side effects and is poorly tolerated in many patients. For instance, in registration trials of pegylated interferon and ribavirin, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients. Major side effects of combination therapy include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. The development of more effective, convenient and tolerated treatments is a major public health objective. Thus, there is a high medical need for low molecular weight compounds that lead to an inhibition of HCV replication. By inhibiting the HCV replication, a rapid reduction in the viral loads of patients infected with the hepatitis C virus is achieved. A reduction of the viral load is a proof of principle of the clinical antiviral activity of HCV inhibitors. By maintaining low to undetectable levels of viral load in patients, disease progression is delayed or even stopped, avoiding thus the development of chronic hepatitis, liver fibrosis, cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma).
Resistance of viruses, and in particular the HCV virus, against inhibitors is also a cause of therapy failure. Many patients receiving anti-HCV therapy do not respond fully to the treatment, mainly because of resistance of the virus to one or more drugs used. Moreover, it has been shown that resistant virus is carried over to newly infected individuals, resulting in severely limited therapy options for these drug-naive patients. Therefore, there is a need in the art for new compounds for antiviral therapy, more particularly for hepatitis therapy. The need in the art is particularly acute for compounds that are active not only on wild type HCV virus, but also on the increasingly more common resistant HCV viruses.
The compounds used in the present invention are derivatives of pyrimidine or triazine. PCT publication WO01/47921 describes pyrimidine and triazine compounds that are inhibitors of kinase activities associated with various inflammatory conditions. In addition, PCT publications WO00/12497 and WO02/076976 describe quinazoline derivatives that are inhibitors of TGFOR receptor kinase and TGF-β mediated signaling.
WO04/087056 relates to bi-cyclic pyrimidine inhibitors of TGF-β, in which a pyrimidine nucleus is bridged at the (5) and (6) position and are further substituted at positions (2) and (4) with substituents comprising aromatic moieties. These compounds are useful in treating subjects with conditions ameliorated by inhibition of TGFβ activity.
WO03/097615 concerns methods of treating fibroproliferative disorders associated with TGF-β signaling, by administering non-peptide small molecule inhibitors of TGF-β specifically binding to the type I TGF-β receptor (TGFβ-R1). The inhibitors are quinazoline derivatives.
WO04/065392 relates to condensed pyridines and pyrimidines and their use as ALK-5 receptor ligands. These compounds are therapeutically active, particularly in the treatment or prophylaxis of disorders characterised by overexpression of transforming growth factor β (TGF-β). Pharmaceutical compositions for use in such therapy are disclosed.
WO03/078426 discloses azolylaminoazines as inhibitors of protein kinases, pharmaceutically acceptable compositions comprising said compounds, and methods of using the compositions in the treatment of various disease, conditions, or disorders.
WO03/078427 discloses azolylaminoazines as inhibitors of protein kinases, pharmaceutically acceptable compositions comprising said compounds, and methods of using the compositions in the treatment of various disease, conditions, or disorders.
WO2003077921 discloses azinylaminoazoles as inhibitors of protein kinases, pharmaceutically acceptable compositions comprising said compounds, and methods of using the compositions in the treatment of various disease, conditions, or disorders.
WO03/078423 discloses compounds useful as inhibitors of protein kinases, pharmaceutically acceptable compositions comprising said compounds, and methods of using the compositions in the treatment of various disease, conditions, or disorders.
WO02/22601 describes pyrazole compositions comprising a pharmaceutically acceptable carrier and compounds which are useful as protein kinase inhibitors, especially as inhibitors of aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer's disease.